This invention relates to a new and useful form of paroxetine hydrochloride (anhydrous) and its preparation thereof.
Canadian Letter Patent 1,287,060 describes two distinct forms of paroxetine hydrochloride viz., an anhydrous form of paroxetine hydrochloride and the hemihydrate form of paroxetine hydrochloride (paroxetine hydrochloride_H2O). The existence of these forms is confirmed in the International Journal of Pharmaceutics, 42, pp. 135-143 and Analytical Proceedings, 25, pp. 305-306, both published in 1988. Canadian Patent Applications Serial No. 2,168,829 (1996) and 2,187,128 (Brantford Chemicals Inc.) (1996) purport to describe several new polymorphs of paroxetine hydrochloride anhydrate.
The two forms described in Canadian Letter Patent 1,287,060, International Journal of Pharmaceutics, 42, pp. 135-143 (1988), and Analytical Proceedings, 25, pp. 305-306 (1988) have been known for a substantial period of time, particularly the anhydrous form, which has a melting point of about 118xc2x0 C. and which is known to be hygroscopic making this material difficult to handle. Coupled with this is the fact that the said anhydrous material is also light and fluffy, which further compounds the problems of handling (filtration and drying) and formulating the active into the final dosage form.
The hemihydrate form is purportedly stable. The purpose of the hemihydrate is to provide material which is less hygroscopic, however the compound does include additional amounts of water. If a suitable form of paroxetine hydrochloride anhydrate was available, it should be easily handled with minimal difficulties with respect to the hygroscopic nature of the material and should not be light and fluffy. Preferably the paroxetine hydrochloride anhydrous would be in a form having a dense structure which enables the raw active to be easily formulated into final dosage form. Such dense material should, of course, also be readily dried and any residual solvents easily removed to yield the bulk active and should be readily adapted for use in the commercial manufacture of anhydrous paroxetine hydrochloride, the active ingredient in the final formulation.
It is therefore an object of this invention to provide such improved paroxetine hydrochloride anhydrous which overcomes the disadvantages of the prior forms of the raw active which suffers from the above deficiencies, particularly the hygroscopic nature of the paroxetine hydrochloride anhydrate, the light fluffy nature of the some forms of paroxetine hydrochloride anhydrate, and the other deficiencies which would deter one from using paroxetine hydrochloride anhydrous and require such person to use the paroxetine hydrochloride hemihydrate in its place.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of examples thereof.
In our research and the research of others, it has been determined that paroxetine hydrochloride anhydrous may exist in a number of polymorphic forms. Our research unexpectedly revealed to us a new amorphous form of paroxetine hydrochloride anhydrous which was very dense, having a bulk density exceeding about 0.6 g/mL and a tapped density exceeding about 0.9 g/mL and which is substantially non-hygroscopic. We have identified this Form as Form IV. Form IV did not retain, we discovered, residual solvent in excess of about 0.1%, even leaving the material exposed to open air for a period of three days (ca. 50% relative humidity), Form IV did not take on moisture more than 1.5% by weight. Form IV, as well, was very stable and was distinguished from the other forms previously described by a melting point between about 81-85xc2x0 C. Furthermore, the conversion of Form IV to the hemihydrate polymorph, as indicated by a differential scanning calorimetry (DSC) maximum of 143xc2x0 C., occurs at a negligible rate even in humid environments. Form IV has the capability of being formulated into final dosage form and is easily manufactured in commercial quantities by processes described in the examples herein.